Summary
Background
The persistence of disseminated tumor cells (DTC) in bone marrow (BM) of breast cancer patients is associated with poor prognosis. Preliminary studies indicated that these patients might benefit from secondary adjuvant targeted therapy. HER2 protein is suggested as one of the most promising targets. The aims of this study were (1) to determine the HER2 status of DTC in BM of breast cancer patients and (2) to compare the HER2 status of DTC and corresponding primary tumors.
Methods
BM aspirates from 137 primary breast cancer patients were included into the study. A double staining procedure was used for the identification of cytokeratin-positive (CK)/HER2 positive cells. HER2 status of the primary tumor was immunohistochemically assessed by the HERCEP-test™.
Results
In 46 of 137 (34%) breast cancer patients CK-positive cells were detectable in BM. DTC with HER2 positivity were found in 20 (43%) of these patients. The HER2 expression on DTC was heterogeneous in 7 of 17 (41%) patients. Concordance rate of HER2 status between primary tumor and DTC was 62%. In 12 of 20 patients with HER2 negative tumors HER2 positive DTC were detected.
Conclusions
HER2 positive DTC can be detected in patients with HER2 negative primary tumors. Therefore, the antigenic profile of DTC may be considered for treatment decision since these patients might actually benefit from trastuzumab. However, the HER2 overexpression on DTC is heterogeneous in individual patients which may reduce the efficacy of an immunotherapy based strategy directed against HER2-antigen only.
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References
Solomayer EF, Diel IJ, Salanti G, Hahn M, Gollan C, Schutz F, Bastert G, Time independence of the prognostic impact of tumor cell detection in the bone marrow of primary breast cancer patientsClin Cancer Res 7: 4102–4108, 2001
Braun S, Pantel K, Muller P, Janni W, Hepp F, Kentenich CR, Gastroph S, Wischnik A, Dimpfl T, Kindermann G, Riethmuller G, Schlimok G, Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancerN Engl J Med 342: 525–533, 2000
Gebauer G, Fehm T, Merkle E, Beck EP, Lang N, Jager W, Epithelial cells in bone marrow of breast cancer patients at time of primary surgery: clinical outcome during long-term follow-upJ Clin Oncol 19: 3669–3674, 2001
Braun S, Kentenich C, Janni W, Hepp F, de Waal J, Willgeroth F, Sommer H, Pantel K, Lack of effect of adjuvant chemotherapy on the elimination of single dormant tumor cells in bone marrow of high-risk breast cancer patientsJ Clin Oncol 18: 80–86, 2000
Janni W, Rack B, Schindlbeck C, Strobl B, Rjosk D, Braun S, Sommer H, Pantel K, Gerber B, Friese K, The persistence of isolated tumor cells in bone marrow from patients with breast carcinoma predicts an increased risk for recurrenceCancer 103: 884–891, 2004
Braun S, Hepp F, Kentenich CR, Janni W, Pantel K, Riethmuller G, Willgeroth F, Sommer HL, Monoclonal antibody therapy with edrecolomab in breast cancer patients: monitoring of elimination of disseminated cytokeratin-positive tumor cells in bone marrowClin Cancer Res 5: 3999–4004, 1999
Schlimok G, Funke I, Holzmann B, Gottlinger G, Schmidt G, Hauser H, Swierkot S, Warnecke HH, Schneider B, Koprowski H, Micrometastatic cancer cells in bone marrow: in vitro detection with anti-cytokeratin and in vivo labeling with anti-17-1A monoclonal antibodiesProc Natl Acad Sci USA84: 8672–8676, 1987
Slamon DJ, Goldolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A, Press MF, Studies of the HER-2/proto-oncogene in human breast cancer and ovarian cancerScience 244: 707–712, 1989
Muss HB, Thor AD, Berry DA, Kute T, Liu ET, Koerner F, Cirrincione CT, Budman DR, Wood WC, Barcos M, Henderson IC, c-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancerN Engl J Med 330: 1260–1266, 1994
Baselga J, Norton L, Albanell J, Kim YM, Mendelsohn J, Recombinant humanized anti-HER2 antibody (Herceptin) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenograftsCancer Res58(13): 2825–2831, 1998
Weiner LM, Monoclonal antibody therapy of cancer. Semin Oncol 26(5 Suppl 14): 43–51, 1999
Piccart-Gebhart MJ: First results of the HERA trial. Session ‘Advances in Monoclonal Antibody Therapy for Breast Cancer’ (Scientific Symposium), ASCO-Meeting, 13–17 May 2005, Orlando, Florida
Di Leo A, Dowsett M, Horten B, Penault-Llorca F, Current status of HER2 testingOncology 63: 25–32, 2003
Edgerton SM, Moore D 2nd, Merkel D, Thor AD, erbB-2 (HER-2) and breast cancer progressionAppl Immunohistochem Mol Morphol11: 214–221, 2003
Gancberg D, Di Leo A, Cardoso F, Rouas G, Pedrocchi M, Paesmans M, Verhest A, Bernard-Marty C, Piccart MJ, Larsimont D, Comparison of HER-2 status between primary breast cancer and corresponding distant metastatic sites Ann Oncol 13: 1036–1043, 2003
Becker S, Becker-Pergola G, Fehm T, Wallwiener D, Solomayer EF, HER2 expression on disseminated tumor cells from bone marrow of breast cancer patientsAnticancer Res 25: 2171–2176, 2005
Wiedswang G, Borgen E, Karesen R, Qvist H, Janbu J, Kvalheim G, Nesland JM, Naume B, Isolated tumor cells in bone marrow three years after diagnosis in disease-free breast cancer patients predict unfavorable clinical outcomeClin Cancer Res10: 5342–5348, 2004
Meng S, Tripathy D, Frenkel EP, Shete S, Naftalis EZ, Huth JF, Beitsch PD, Leitch M, Hoover S, Euhus D, Haley B, Morrison L, Fleming TP, Herlyn D, Terstappen LW, Fehm T, Tucker TF, Lane N, Wang J, Uhr JW, Circulating tumor cells in patients with breast cancer dormancyClin Cancer Res 10: 8152–8162, 2004
Muller V, Stahmann N, Riethdorf S, Rau T, Zabel T, Goetz A, Janicke F, Pantel K, Stahmann N, Riethdorf S, Rau T, Zabel T, Goetz A, Janicke F, Pantel K, Circulating tumor cells in breast cancer: correlation to bone marrow micrometastases, heterogeneous response to systemic therapy and low proliferative activityClin Cancer Res11: 3678–3685, 2005
Pantel K, Schlimok G, Braun S, Kutter D, Lindemann F, Schaller G, Funke I, Izbicki JR, Riethmuller G, Differential expression of proliferated – associated molecules in individual micrometastatic carcinoma cells J Natl Cancer Inst85: 1419–1423, 1993
Vogel C, Cobleigh M, Tripathy D, Gutheil J, Harris LN, Fehrenbacher L, Slamon DJ, Murphy M, Novotny WF, Burchmore M, Shak S, Stewart SJ, Press M, Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer J Clin Oncol 20: 719–726, 2002
Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, Wolter JM, Paton V, Shak S, Lieberman G, Slamon DJ, Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease J Clin Oncol 17: 2639–2648, 1999
Romond E: Joint analysis of NSABP-B-31 and NCCTG-N9831; Session ‘Advances in Monoclonal Antibody Therapy for Breast Cancer’ (Scientific Symposium), ASCO-Meeting, 13–17 May 2005, Orlando, Florida
Braun S, Schlimok G, Heumos I, Schaller G, Riethdorf L, Riethmuller G, Pantel K, ErbB2 overexpression on occult metastatic cells in bone marrow predicts poor clinical outcome of stage I-III breast cancer patients Cancer Res61: 1890–1895, 2001
Meng S, Tripathy D, Shete S, Ashfaq R, Haley B, Perkins S, Beitsch P, Khan A, Euhus D, Osborne C, Frenkel E, Hoover S, Leitch M, Clifford E, Vitetta E, Morrison L, Herlyn D, Terstappen LW, Fleming T, Fehm T, Tucker T, Lane N, Wang J, Uhr J, HER-2 gene amplification can be acquired as breast cancer progressesProc Natl Acad Sci USA101: 9393–9398, 2004
Tanner M, Jarvinen P, Isola J, Amplification of HER-2/neu and topoisomerase II alpha in primary and metastatic breast cancer Cancer Res 61: 5345–5348, 2001
Brandt B, Roetger A, Heidl S, Jackisch C, Lelle RJ, Assmann G, Zanker KS, Isolation of blood-borne epithelium-derived c-erbB-2 oncoprotein-positive clustered cells from the peripheral blood of breast cancer patients Int J Cancer 76: 824–828, 1998
Seidman AD, Berry D, Cirrincione C, Harris L, Dressler L, Muss H, Naughton M, Norton L, Winer E, Hudis C, CALGB 9840: Phase III study of weekly (W) paclitaxel (P) via 1-hour(h) infusion versus standard (S) 3h infusion every third week in the treatment of metastatic breast cancer (MBC), with trastuzumab (T) for HER2 positive MBC and randomized for T in HER2 normal MBC J Clin Oncol 22(14S): 512, 2004
Hayes DF, Walker TM, Singh B, Vitetta ES, Uhr JW, Gross S, Rao C, Doyle GV, Terstappen LW, Monitoring expression of HER-2 on circulating epithelial cells in patients with advanced breast cancer Int J Oncol 21: 1111–1117, 2002
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Solomayer, E., Becker, S., Pergola-Becker, G. et al. Comparison of HER2 status between primary tumor and disseminated tumor cells in␣primary breast cancer patients. Breast Cancer Res Treat 98, 179–184 (2006). https://doi.org/10.1007/s10549-005-9147-y
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DOI: https://doi.org/10.1007/s10549-005-9147-y